Muscle weakness due to limited neuromuscular input or failure of signal transmission at the neuromuscular junction can result in significant functional disability and increased mortality in several diseases called motor neuron diseases. Such motor neuron diseases include, for example, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and myasthenia gravis (MG). Amyotrophic lateral sclerosis (ALS) is a degenerative disease of upper and lower motor neurons that initially leads to progressing muscle dysfunction and ultimately to muscle paralysis. Disease progression is typically fairly linear, and death from respiratory failure occurs 3-5 years from onset. However, there can be variability in the progression rate within individual patients and also in survival between patients (Caroscio J T et al., Neurol Clin 5(1), 1987, 1-8).
Unfortunately, there are few evidence-based options for slowing disease progression or improving quality of life for patients affected by ALS (Miller R G et al., Neurology 73(15), 2009, 1218-1226). Although slowing disease progression is vitally important, a therapy that improves functional performance would benefit patients with ALS even if it does not directly alter the underlying pathophysiologic basis of the disease. Despite significant efforts there are still no therapies on the market that improve neuromuscular function. Thus, if the response of muscle to neural input or the force and endurance of muscle contraction could be enhanced therapeutically, the functional status of ALS patients could be directly maintained or improved, even if their underlying disease process continues.
Levosimendan, which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, is currently used for the short term treatment of patients who suffer from acutely decompensated severe heart failure. Levosimendan increases contractility of the heart by enhancing the sensitivity of cardiac myofilaments to calcium. Levosimendan has an active metabolite (R)—N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-acetamide (II) which is present in man following administration of levosimendan. The sustained hemodynamic effects of levosimendan are due to the active metabolite (II). See Szilagyi S, et al., Eur J Pharmacol. 2004, 486(1):67-74; Kivikko M, et al., Circulation, 2003, 107(1):81-6.
There is an urgent need for medicaments which are able to improve functional status of patients suffering from motor neuron diseases such as ALS.